Synthesis of a-silylcarbinols from cyclic ketones using trialkylsilyl-lithium is a very useful procedure in synthetic organic chemistry. The base-induced cleavage of carbon-silicon bonds in a-silylcarbinol which results in protiodesilylation is known as the Brook rearrangement, and has been shown to proceed with retention of configuration at the carbon atom. The resulting a-silylcarbinol can be expected to rearrange to the corresponding silyl enol ether fairly readily in the presence of base and an electrophile (e.g. protons). The removal of the trialkylsilyl group from the oxygen in the presence of base in methanol generates the secondary alcohol. Hence, a general method for tritium labelling is available by the use of tritiated water as the electrophile, and we expect this will be an efficient procedure for the regioselective labelling of many biologically important compounds. Our initial approach involved the preparation of an appropriate a-silylcarbinol by the reaction of 4-phenyl cyclohexanone and trimethylsilyllithium. The latter was made from the cleavage of the weak Si-Si bond in hexamethyldisilane with methyllithium in HMPA at low temperature. Addition of the model ketone to this mixture generated the corresponding silylcarbinol, but in unsatisfactory (10%) yield. A second approach was the synthesis of a more reactive reagent, dimethylphenylsilyl lithium and addition of this reagent to 4-phenyl cyclohexanone and 4-t-butyl cyclohexanone to give the corresponding a-silyl carbinols in about 59% and 75% yield respectively. The widespread use of dimethylsulfoxide as a solvent for the Brook rearrangement was found to be inappropriate for deuterium or tritium labelling reactions, since the methyl hydrogens of DMSO are readily exchangeable under basic conditions. A variety of solvents were examined, and dry DMF and dry THF were found the best for the current application. Potassium-t-butoxide was used as the base in these experiments. In our exploratory labelling experiments, a mixture of the substrate and the base was dissolved in dry THF and stirred at room temperature for 5 minutes before quenching with a solution of deuteriated water in THF or DMF. Repeated experiments with this method under very dry conditions gave very high chemical yield (100%) of exclusively the axial isomer, but surprisingly no deuterium incorporation. These results indicated that the intermediate carbanion must have been protonated from a different source in the reaction before the addition of the electrophile (D2O). We approached this problem by doing the experiments in a different way in which the substrate, 4-phenyl silylcarbinol, and the base were mixed, but not dissolved in THF. A solution of deuteriated water in THF was then added dropwise to the solid form over about 5 minutes and the mixture was stirred for 30 min. After hydrolysis of the silyl enol ether in methanol with the excess of base present in the reaction mixture, the proton NMR analysis revealed that the reaction again exclusively yielded the axial isomer of 4-phenyl cyclohexan-1-ol with 50-54% deuterium incorporation at the C-1 position. The deuterium content was also measured by mass spectrometry, confirming the NMR results. To confirm the stereoselectivity of the procedure, proton NMR analysis of the product was compared with a mixture of axial and equatorial isomers formed by a literature reduction of 4-phenyl cyclohexanone with lithium aluminum hydride. The pure axial isomer was also synthesized by other methods, and its NMR spectrum used to confirm the other data. Therefore, we adapted this method as our labelling technique and the Brook rearrangement conditions were applied to the silylcarbinol derived from 4-t-butyl cyclohexanone, giving similar results. A third substrate was cholest-5-ene-3b-dimethylphenylsilyl-3a-ol synthesized from cholest-5-ene-3-one. Again using D2O as the electrophile, careful NMR analysis of the product showed it to be exclusively cholest-5-ene[3b-2H]-3a-ol (epicholesterol), thus confirming retention of configuration at the carbon atom during the Brook rearrangement. Having established that the reaction works under deuteriation conditions, we applied the reaction to the analogous tritiation of the three substrates with the newly developed method using high specific activity tritiated water as the electrophile. All the experiments generated exclusively the axial isomers of the desired products with 36-55% 3H incorporation, varying with the substrate. GC analysis of tritiated epicholesterol required silyl derivatization to make it sufficiently volatile. Trimethylsilyl-[3H]epicholesterol was prepared by reaction of the tritiated substrate and N,O-bis-(trimethylsilyl)acetamide in pyridine, and the GC/LSC analysis revealed a specific activity of 15.4 Ci/mmole, with 34% yield. Our final example for this project is the preparation of 4,4-diphenylcyclohex-2-ene-1-dimethylphenylsilyl-1-ol or 4,4-dimethylcyclohex-2-ene-1-dimethylphenylsilyl-1-ol from the corresponding cyclic a,b-unsaturated ketones. These precursors were prepared under different reaction conditions than the previous ketones and are now under investigation to explore the feasibility for introduction of tritium into the g-position of the cyclohex-1-en-1-ol product. Application of the Brook rearrangement to tritium labelling has given rise to a highly regioselective and stereoselective tritiation method. The demonstration tritium labelling experiments are in their final phase.